Impaired performance of skeletal muscle in α‐glucosidase knockout mice

Abstract

Glycogen storage disease type II (GSD II) is an inherited progressive muscle disease in which lack of functional acid alpha-glucosidase (AGLU) results in lysosomal accumulation of glycogen. We report on the impact of a null mutation of the acid alpha-glucosidase gene (AGLU(-/-)) in mice on the force production capabilities, contractile mass, oxidative capacity, energy status, morphology, and desmin content of skeletal muscle. Muscle function was assessed in halothane-anesthetized animals, using a recently designed murine isometric dynamometer. Maximal torque production during single tetanic contraction was 50% lower in the knockout mice than in wild type. Loss of developed torque was found to be disproportionate to the 20% loss in muscle mass. During a series of supramaximal contraction, fatigue, expressed as percentile decline of developed torque, did not differ between AGLU(-/-) mice and age-matched controls. Muscle oxidative capacity, energy status, and protein content (normalized to either dry or wet weight) were not changed in knockout mice compared to control. Alterations in muscle cell morphology were clearly visible. Desmin content was increased, whereas alpha-actinin was not. As the decline in muscle mass is insufficient to explain the degree in decline of mechanical performance, we hypothesize that the large clusters of noncontractile material present in the cytoplasm hamper longitudinal force transmission, and hence muscle contractile function. The increase in muscular desmin content is most likely reflecting adaptations to altered intracellular force transmission.

Physical therapy management of Pompe disease

“…14 Protein catabolism and abnormal protein metabolism may occur, due to or exacerbated by poor nutrition, with more rapid clearance of branched chain amino acids that normally have a role in muscle protein synthesis. [15][16][17][18] Muscle function may be impaired by loss of contractile mass, decreased contractile function due to clusters of non-contractile material (glycogen) impeding force transmission by interrupting or displacing myofibrils, 12,19,20 decreased oxidative capacity resulting in decreased adenosine-5=-triphosphate (ATP) availability for contraction, and impaired innervation. 21 Clinical presentation and distribution of muscle weakness Weakness in Pompe disease is greater in proximal muscles than distal, greater in lower extremities (LE's) than upper extremities (UE's), and generally symmetrical but imbalanced across joints.…”

A modified PAS stain combined with immunofluorescence for quantitative analyses of glycogen in muscle sections

“…Patients suffering from this disease are characterised by severe muscle wasting and muscle weakness (DiMauro and Lamperti 2001). In a mouse model mimicking GSDII (GSDII mice), the gene encoding for 1,4-a-glucosidase has been knocked out, giving rise to a pathology very similar to GSDII, including lysosomal glycogen accumulation and muscle weakness (Bijvoet et al 1999;Hesselink et al 2002), with an increased number of apoptotic nuclei as a putatively important player (Hesselink et al 2003). Histological examination of the subcellular storage sites and the abundance of muscle glycogen, together with (immuno)fluorescence microscopy to examine localisation and expression of many distinct proteins, may turn out to be a valuable, however presently unavailable, tool to study this hypothesis.…”

Age‐related decline in muscle strength and power output in acid 1–4 α‐glucosidase knockout mice

“…In general, differences in shortening velocity are caused by differences in muscle fiber-type composition. In AGLU Ϫ/Ϫ mice, however, the fiber-type composition does not differ from age-matched controls, 14 suggesting that in AGLU Ϫ/Ϫ mice the effect of changes in fiber-type composition on optimal shortening angular velocity is negligible. It is conceivable that, in AGLU Ϫ/Ϫ mice, the presence of glycogen-filled lysosomes causes a decrease in optimal shortening velocity.…”

“…Micromorphological alterations such as clusters of noncontractile material and changes in cytoskeleton composition may be important in the decreased quality of muscle tissue in GSD II. 11,12,14 Validity of Mouse Model of GSD II. The AGLU Ϫ/Ϫ mouse model used in the present study almost completely lacked activity of the lysosomal enzyme acid 1-4 ␣-glucosidase, comparable to the most severe, infantile form of the human disease.…”